One same initiating molecule and two divided downstream pathways? — Mechanism of aluminum-induced programmed neural cell necrosis

Objective: The research is to elucidate the mechanism of programmed neuronal necrosis induced by aluminum exposure. The mechanism of programmed neuronal cell necrosis caused by aluminum exposure is due to the key death proteins RIP1, RIP3, MLKL and CaMKⅡ in vivo and vitro experiments. Methods In vivo study, mice were intraperitoneally injected with freshly prepared maltol aluminum for two months to establish aluminum-induced cognitive impairment model. The key death related proteins were measured by Western blot and the relationships between those proteins were detected by IP. LDH release was used to show the cell death, and ROS indicated the damage of brain. In Al-exposed SH-SY5Y cells, GSK'872 was interfered to observe the expression of key death related proteins by WB and IP, as well as PI dyeing. Besides, NSA and KN-93 were administered to detect the LDH release and ROS change, including mitochondrial membrane potential variation in the Al-exposed cells. Results Expression of RIP1, RIP3, MLKL and CaMKⅡ proteins were increased in vivo and vitro study after aluminum exposure. Inhibition of RIP3, MLKL and CaMKⅡ protein expression could reduce PI stained cells and LDH release. ROS declined after administration of GSK'872 and NSA in Al-exposed cells, while mitochondrial membrane potential elevated after intervention of KN-93 in Al-exposed cells with decreased mitochondrial membrane potential. Conclusion Programmed neuronal necrosis was one of the main causes though that aluminum lead to neuron reduction. The signal pathways involved in programmed necrosis were RIP1-RIP3-MLKL and RIP1-RIP3-CaMKⅡ pathways, one same initiating molecule – RIP1, two downstream pathways: RIP3-MLKL pathway and RIP3-CaMKII pathway.